Altered brain activity during pain processing in fibromyalgia

Abstract

Fibromyalgia syndrome (FMS) is characterized by widespread pain. Studies with functional neuroimaging support the hypothesis of central pain augmentation in FMS. We tested this in our study with a novel paradigm of tonic pain induced by a single stimulus. Tonic pain, in contrast to phasic pain, seems to be a more appropriate experimental approach to study adaptive mechanisms of pain processing in FMS. We hypothesized that brain areas related to the “medial” pain system and the amygdalae will present different activation in patients compared to healthy subjects. An fMRI-block design before, during and after an incision was made in patients with FMS and in healthy controls. Acute pain caused by the incision was measured during the course of the experiment. A 2 factorial model of BOLD-signal changes was designed to explore significant differences of brain activation between both groups during the pain stimulus. Additionally the first Eigenvariates in those areas which show an interaction between both factors were determined over the time course of pain stimulation. Differences of activation in the fronto-cingulate cortex, the supplemental motor areas, and the thalamus were found between both groups with distinct differences in BOLD-signals changes over the time course of pain stimulation, even during anticipation of pain. Our results support the hypothesis that central mechanisms of pain processing in the medial pain system, favourable cognitive/affective factors even during the anticipation of pain, may play an important role for pain processing in patients with FMS.

Introduction

Fibromyalgia syndrome (FMS) is a pain syndrome characterized by widespread musculoskeletal pain and diffuse tenderness at multiple tenderpoints (Wolfe et al., 1990). Patients with FMS present lower pain thresholds and report higher pain ratings than healthy controls in response to different stimuli (Desmeules et al., 2003, Granges and Littlejohn, 1993, Petzke et al., 2003). The etiology of this chronic pain condition is largely unknown.

Functional imaging during experimental pain with functional magnetic resonance imaging (fMRI) presented similar brain activation in regions involved in pain processing in patients with FMS and healthy controls, however with increased pain sensitivity and brain activation in comparison to healthy controls during comparable stimulus (Gracely et al., 2002). In another study, increased brain activity in FMS compared to controls during non-painful stimuli was detected, with greatest differences in regions involved in processing of sensory, cognitive and emotional aspects of pain (Cook et al., 2004). Additionally, a cognitive style of catastrophizing, that means responses to pain will be perceived as being awful, horrible and unbearable, in patients with FMS was associated with the activity in brain areas related to anticipation of pain (medial frontal cortex, cerebellum), attention to pain (dorsal ACC, dorsolateral–prefrontal cortex), motor control and emotional aspects of pain (claustrum) (Gracely et al., 2004). Additionally, Giesecke et al. (2005) found amygdala activation during pressure pain restricted to the subset of FMS patients with comorbid depression.

Functional brain imaging in healthy controls has identified a complex network of brain areas involved in serial and parallel pain processing (for overview see (Porro, 2003, Treede et al., 1999)): Areas of the “lateral pain system”, mainly attributed to the sensory-discriminative component of pain (sensory cortex, inferior parietal cortex, posterior insula) are related to mechanisms of stimulus localization, intensity and quality discrimination. Parts of the cingulate cortex, anterior insula, and frontal cortex, attributed to the ”medial pain system”, are mainly related to affective–motivational components of pain, e.g. its unpleasantness. Furthermore, studies provided important information about influences of psychological mechanisms (e.g. cognition, attention, anticipation, emotion) on pain processing in healthy subjects (Bantick et al., 2002, Ploghaus et al., 2003, Porro et al., 2003, Wager et al., 2004). The amygdalae, for which no definite functional allocation into the pain network has been established so far, seem to be important in pain processing in regard of cognitive factors of pain anticipation (Tracey, 2005, Bernard et al., 1992, Hadjipavlou et al., 2006).

In patients with chronic pain disorders, like in FMS, a major question is about the factors which are important in the transition from acute to chronic pain. In regard of the results of functional imaging (Cook et al., 2004, Gracely et al., 2004, Giesecke et al., 2005) and other studies (Thieme et al., 2005, Giesecke et al., 2003, Montoya et al., 2005) in patients with FMS it is very much reasonable to suspect central sensitization due to affective/cognitive factors as important constitutes in the transition from acute to chronic pain in FMS.

All fMRI studies in FMS published so far used repetitive phasic noxious stimuli to induce pain in “block-designs”. A growing body of evidence indicates that the neurobiological mechanisms of acute pain perception are at least partially different from that seen in chronic clinical pain conditions. Moreover chronic pain engages brain regions critical for cognitive/emotional assessments (for review see Apkarian et al., 2005). When answering the question whether affective/cognitive factors may play an important role in FMS, which seem to be related to more subtle changes in brain activity, a tonic pain as an experimental approximation to chronic pain may be more appropriate in detecting the temporal changes of brain activation in adaptation of pain (Wiech et al., 2005).

Kawamata et al. (2002) introduced a new kind of a pain model in humans by performing an incision at the volar forearm which is thought to be related to peripheral and central sensitization mechanisms and causes a pain which decreases over several minutes. With this new pain model of tonic pain we expected to detect subtle and adaptive mechanisms of pain processing in functional imaging in a population of patients with a chronic pain disorder.

We hypothesized that during the course of pain experience brain areas of the “medial” pain system, including the amygdalae, as important areas in pain anticipation and affective/cognitive processing, will present differing activation in patients with FMS compared to healthy subjects. Differences between patients with FMS and healthy controls should occur even in the time of anticipation of pain and without the presence of a painful stimulation.